Chapter 197 – Disorders of Supranuclear Control of Ocular Motility

• Loss of voluntary saccades (fast) and pursuit (slow) eye movements may result from interruption of neural pathways that carry commands from the cerebral cortex to the ocular motor nuclei in the brainstem.

• Disconjugate eye movement disorders and gaze palsies may result from lesions that involve the prenuclear pathways between the gaze centers and the ocular motor nuclei.

With the exception of reflex eye movements (vestibulo-ocular and optokinetic) and the fast phases of nystagmus, cerebral structures determine when and where the eyes move, while brainstem centers determine how they move.[1]

The final common pathways for eye movements are located in “gaze centers” in the brainstem ( Fig. 197-1 ). The paramedian pontine reticular formation (PPRF) contains the premotor substrate for ipsilateral horizontal gaze. The midbrain reticular formation (MRF) mediates vertical gaze, vergence eye movements, and ocular counter rolling ( Fig. 197-2 ). The PPRF and MRF receive input from a number of “higher” centers, including areas in the cerebral hemispheres, superior colliculus, vestibular nuclei, and cerebellum (see Fig. 197-1 ); they, in turn, innervate the three ocular motor nuclei to generate appropriate eye movements. Supranuclear gaze palsies result from interruption of the neural pathways that carry commands for voluntary saccades and pursuit before they reach the eye movement “generators” in the brainstem.

Sound knowledge of the anatomy of eye movement control systems and of normal types of eye movements is necessary to localize accurately lesions that impair ocular motility.

Figure 197-1 Supranuclear control of eye movements. The pontine horizontal gaze center (blue) and the vertical gaze center in the midbrain (yellow) receive input from the frontal eye fields to initiate saccades, and from the parieto-occipito-temporal junction to control pursuit. These gaze centers control ocular motility by relaying to the ocular motor nerve nuclei (III, IV, and VI).

ANATOMY OF EYE MOVEMENT

Anatomy of Supranuclear Eye Movement Control

Eye movements are divided broadly into the following two types ( Box 197-1 ):

• Fast eye movements, or saccades, that move the eyes from one target to another at velocities of up to 800°/second

• Slow eye movements that allow the eyes to follow (hold) a target when either the target, the head, or both are moving

Slow eye movements may be conjugate (e.g., pursuit, see below) or disconjugate (e.g., vergence eye movements that are necessary for binocular single vision and stereoscopic depth perception when a target moves toward or away from the subject). The latency for saccades is about 225?msec, and pursuit latency is about 125?msec.2 The initiation and generation of saccadic and pursuit eye movements is complex and dealt with in greater detail elsewhere[1] [3] ; a simplified overview is given here. The fast phases of nystagmus ( Chapter 202 ) also are saccades (see Box 197-1 ).

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Figure 197-2 Eye position during head tilt. The normal ocular counter-rolling reflex maintains relative eye position when the head is tilted. As the head tilts to the left, the right eye excyclotorts and depresses while the left eye rises and incyclotorts. The ocular tilt reaction occurs after stroke and is paradoxical. Patients have a head tilt, bilateral torsion, and a sense of a tilted vertical meridian, all to the same side.

Types of Eye Movements

SACCADES OR FAST EYE MOVEMENTS (VELOCITY UP TO 800°/SEC)

Voluntary (internally triggered)

Reflexive (externally triggered—by visual or auditory stimuli)

Spontaneous (searching, rapid eye movements of sleep)

Fast phases of nystagmus (physiological or pathological)

SLOW EYE MOVEMENTS (VELOCITY UP TO 70°/SEC)

Smooth pursuit

• Foveal pursuit

• Full-field pursuit (optokinetic slow phase)

Vestibular slow phase (includes torsional movements)

Vergence

OTHER OCULAR OSCILLATIONS (E.G., OPSOCLONUS, FLUTTER)

Horizontal Eye Movements

The contralateral frontal lobe, particularly the frontal eye field, is responsible for generating horizontal saccades. Each frontal eye field projects to the contralateral PPRF, which in turn innervates the abducens nucleus. Pursuit eye movements are triggered by the ipsilateral posterior parietal lobe (see Fig. 197-1 ), which also projects to the PPRF and then to the abducens nucleus. About 60% of the neurons in the abducens nucleus innervate the ipsilateral lateral rectus muscle; the remaining 40% are interneurons that project, via the medial longitudinal fasciculus (MLF), to the contralateral medial rectus subnucleus in the oculomotor nuclear complex ( Fig. 197-3 ). Thus, activation of the PPRF or the abducens nucleus generates ipsilateral horizontal gaze; conversely, damage to either of these structures results in an ipsilateral gaze palsy. The PPRF also receives input from the ipsilateral posterior parietal lobe, the vestibular system, the superior colliculus,

Figure 197-3 Vestibulo-ocular reflex and its contribution to horizontal eye movements. The semicircular canals respond to rotational acceleration of the head by driving the vestibulo-ocular reflex to maintain the eyes in the same direction in space during head movement. Fibers from the horizontal semicircular canal travel first to the vestibular nuclei and then to each paramedian pontine reticular formation. Excitatory projections that travel to the contralateral sixth cranial nerve nucleus and, via the medial longitudinal fasciculus, to the ipsilateral medial rectus subnucleus cause gaze to the left. In a similar manner, inhibitory projections are sent to the antagonist ipsilateral lateral rectus and contralateral medial rectus.

and the cerebellum, all of which play a role in generating saccades.

Vertical Eye Movements

The premotor substrate for vertical gaze lies in the MRF, although some vertical saccades are programmed in the PPRF and relayed to the MRF, presumably to coordinate horizontal, vertical, and oblique trajectories. The rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) contains neurons for both upward and downward saccades. Their axons relay to neurons in the interstitial nucleus of Cajal, which discharge in relation to vertical eye position and play a role in vertical pursuit and eye position. The neurons for upward saccades innervate both ipsilateral and contralateral oculomotor and trochlear nerve nuclei ( Fig. 197-4 ). The neurons that mediate downward saccades only innervate the oculomotor and trochlear nerve nuclei bilaterally (see Fig. 197-1 ). The riMLF and the interstitial nucleus of Cajal also are involved in the generation of ipsilateral torsional eye movements.

The supranuclear pathways for vertical saccades travel from both frontal eye fields to innervate the riMLF on each side in the MRF (see Fig. 197-4 ). Vertical saccades require simultaneous activation of both frontal eye fields.

Slow Eye Movements

Slow eye movements help maintain fixation on a target in order to stabilize the image on the fovea when either the subject or object is moving. Four types of slow eye movements occur, namely pursuit, optokinetic, vestibular, and vergence.

Pursuit Eye Movements

Pursuit eye movements allow the eyes to track a moving object at velocities up to 70°/second and have a latency of about

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Figure 197-4 Pathways for vertical gaze. Upgaze pathways originate in the rostral interstitial nucleus of the medial longitudinal fasciculus and project to innervate the oculomotor and trochlear nerves bilaterally. Upgaze paralysis is a feature of the dorsal midbrain syndrome as a result of the lesion’s effect on the posterior commissure (lesion A). Downgaze pathways also originate in the rostral interstitial nucleus of the medial longitudinal fasciculus but probably travel more ventrally. Bilateral lesions affect downgaze more severely than unilateral lesions and usually are located dorsomedial to the red nucleus. INC, Interstitial nucleus of Cajal; IO, inferior oblique subnucleus; IR, inferior rectus subnucleus; PC, posterior commissure; riMLF, rostral interstitial nucleus of the medial longitudinal fasciculus; RN, red nucleus; SR, superior rectus subnucleus.

125?msec.2 The generation of pursuit eye movement is complex[1] [3] but consists of three essential elements as follows:

• A sensory component driven by an image moving across the fovea

• A motor component generated largely by the posterior parietal lobe (parieto–occipito–temporal junction) that projects to the PPRF on the same side and is responsible for ipsilateral tracking movements

• An attentional–spatial component for concentration on selected targets, orientation in space

The precise route for the pursuit pathways from the parieto–occipito–temporal junction to the PPRF is not clear, but the ipsilateral pontine nuclei and the vestibulocerebellum have important modulatory influences. Vertical smooth pursuit is even less well understood.

Vestibular System

Vestibular eye movements maintain foveation when the head moves in any direction or plane, including the horizontal (yaw), vertical–sagittal (pitch), or vertical–coronal (roll) planes. For example, if the subject’s head turns 10 degrees to the right, the eyes rotate 10 degrees to the left to maintain fixation (see Fig. 197-2 ). The latency for vestibular responses is about 10?msec.

Optokinetic System

The optokinetic system complements the vestibulo-ocular system when it becomes inadequate, such as with sustained head rotation when the eyes reach the limit in the orbit, or during very slow head movements when the vestibulo-ocular reflex (VOR) is less responsive. In humans the optokinetic system is tested predominantly by foveal fixation and pursuit and, to a lesser extent, by full visual field stimulation which is compelling and largely involuntary. The latter is tested clinically by rotating an image of the environment around the patient or by turning the patient in a revolving chair so the environment appears to be moving relative to the patient.

Vergence System

The vergence system enables eyes to move disconjugately in the horizontal plane and allows binocular fixation of an object that moves toward (convergence) or away (divergence) from the subject. The main stimuli for vergence movements are retinal blur (object unfocused) and diplopia (fusional disparity); convergence is associated with accommodation and pupillary miosis (the near triad). The pathways that generate vergence eye movements are not known precisely, but the occipital lobe, midbrain, and cerebellum play significant roles.

DIAGNOSTIC TESTING

Techniques used in the examination of the ocular motor system fall into six categories, reviewed in detail by Borchert.[4]

Saccades

The patient is asked to alternate fixation rapidly between two targets, such as a finger and the examiner’s nose. Both horizontal and vertical saccades are tested and the following three observations are made:

• The latency to saccadic initiation

• The relative velocity of the saccade

• The accuracy of the saccade

Abnormalities in saccadic accuracy include overshooting or undershooting the target and are referred to as saccadic dysmetria. Gross abnormalities are clinically obvious, but detection of subtle changes require quantitative oculography.[3]

Fixation

The patient looks at a stationary, accommodative target projected in the distance, while the examiner checks fixation both monocularly and binocularly. Fixation should be steady without nystagmus or other significant ocular oscillations or intrusions, such as flutter or opsoclonus. Small eye movements, such as square wave jerks of less than 1–2 degrees, and micromovements, such as microsaccades, microdrift, and ocular microtremor, are normal and do not interrupt fixation.[5]

Pursuit

The patient is asked to fixate a small object, such as a pencil, and follow it slowly through the extent of horizontal and vertical versions; the patient’s eyes should pursue the target smoothly. If the pursuit system is defective, or the target moves too quickly, the eyes fall behind and make “catch-up saccades” to refixate the target. This produces saccadic, or cogwheel, pursuit. The extent of versions and ductions may be determined while testing pursuit.

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Pursuit also may be evaluated while testing the patient’s ability to suppress the VOR. Have the patient sit on a rotatable stool and fixate one of his or her own thumbs at arm’s length, then rotate the stool so that the patient’s head, arm, and thumb move as one. A normal patient can suppress the induced VOR by maintaining fixation on the thumb, even in darkness or with the eyes closed—VOR suppression probably involves the same pathways as smooth pursuit. [6] Because blind patients also can suppress the VOR, this technique particularly helps to differentiate between real and psychogenic visual deficits—psychogenic patients appear unable to follow a target smoothly.

Vergence Eye Movements

A target is moved toward (convergence) and then away (divergence) from the patient, who follows it.

Ocular Alignment

Ocular alignment is covered in more detail in the section on strabismus ( Chapter 70 ). Ocular alignment should be determined by simultaneous prism and cover testing (for tropias) and by alternate cover testing (for phorias, and to measure the basic deviation). Cover testing must be performed with the patient wearing the full cycloplegic refraction, and fixation must be maintained on the smallest readable optotype (an accommodative target). To determine if horizontal deviations are comitant, cover testing should be performed in at least five of the cardinal positions of gaze and at near. Patients with vertical deviations should be checked in the right and left head tilt positions, as well.

Differentiating Supranuclear from Nuclear and Infranuclear Lesions

If the patient has a gaze palsy, the physician determines whether the eyes can be moved reflexively in the direction of the “paralysis” by testing the oculocephalic (Doll’s eyes) reflex or the vestibulo-ocular reflex using caloric stimulation of the tympanic membrane.

Oculocephalic (Doll’s Eyes) Reflex

The oculocephalic (Doll’s eyes) reflex is performed by getting the patient to tilt the head forward 30 degrees and fixate on a distant target. The head is then rotated in the direction opposite the gaze palsy. This maneuver uses direct projections from the vestibular system to the ocular motor nuclei to move the eyes reflexively (see Fig. 197-3 ). Gaze palsies caused by lesions of the cerebral cortex can be overcome by vestibulo-ocular testing, except during the acute phase (diaschisis). However, with paranuclear, nuclear, or infranuclear lesions, the reflex does not overcome the gaze palsy. This test should not be performed if the neck is unstable or has not been cleared (i.e., cervical spine instability has been ruled out) after trauma.

Vestibulo-ocular Reflex Testing

The patient’s head is tilted back 60° and the external auditory meatus irrigated with either cool or warm water to stimulate the horizontal semicircular canal. In normal subjects and patients who have supranuclear gaze palsies, cool water stimulation causes the eyes to deviate slowly toward the irrigated side, which results in nystagmus with the fast (corrective) phase to the opposite side. When warm water is used the fast phase is toward the stimulated ear. The mnemonic COWS (cool, opposite, warm, same) refers to the direction of the fast phase of the nystagmus. In comatose patients no corrective (fast) phase occurs, so with cold water the eyes deviate tonically toward the irrigated ear. Simultaneous bilateral caloric testing may be used to evaluate vertical eye movements, but this is less reliable than oculocephalic testing.[4] If the tympanic membrane is perforated, oxygen piped through ice should be used instead of water.

DISORDERS OF SUPRANUCLEAR OCULAR MOTILITY

Supranuclear ocular motility disturbances result from interruption of the neural pathways carrying commands for voluntary saccades, pursuit, and vergence before they reach the brainstem eye movement generators. They may be divided into two groups—disorders of gaze and disorders of vergence eye movements. Gaze palsies affect conjugate eye movements and are characterized by loss of voluntary gaze, in one or more directions, while sparing reflex movements, such as the VOR, optokinetic nystagmus (OKN), and Bell’s phenomenon. Disorders of vergence eye movements are disconjugate. Skew deviation and the ocular tilt reaction, which also spare the final common pathway for extraocular eye movements and are technically supranuclear, may also affect reflex eye movements and are referred to in this chapter as prenuclear.[1]

Congenital Gaze Palsies

Congenital ocular motor apraxia (COMA) or, more correctly, congenital saccadic palsy,[5] [7] is more common in boys than in girls; these children find it difficult to initiate saccades and have variable impairment of pursuit. Reflex slow phases of OKN and the VOR are intact, but fast (saccadic) phases often are impaired, especially in children. Vertical eye movements remain intact. In early infancy, blindness may be suspected because of the inability to fixate or follow objects. However, after a few months head control is achieved and the patient moves the eyes by thrusting the head in the direction of the target. As the head overshoots the target, the eyes follow the head movement and eventually take up fixation on the new target. The head thrusts, usually accompanied with blinks, become less prominent with time. Confirmation of saccadic palsy is made by spinning the infant around the examiner ( Fig. 197-5 ).[8] The eyes move conjugately and slowly in the direction of the spin but, because of the impaired saccades, no corrective horizontal fast phases are seen. Occasionally, torsional or vertical saccades occur instead. COMA may be associated with abnormalities in the cerebellum and posterior fossa, and it may be associated with other features of developmental delay. Ocular motor disorders resembling COMA may be seen in a number of conditions, including Aicardi’s syndrome, dysgenesis of the corpus callosum or cerebellum or both, ataxia telangiectasia (autosomal recessive),

Figure 197-5 The child is spun around the examiner to test the vestibulo-ocular reflex. The slow tonic phase produces gaze in the direction of the spin; fast phase corrective saccades occur to drive the eyes back. In congenital ocular motor apraxia (congenital saccadic palsy), fast phases are absent and the eyes are driven tonically in the direction of the spin.

Acquired horizontal supranuclear gaze palsies may occur with stroke, head injury, tumors, seizures, and, rarely, with metabolic disease such as Gaucher’s type I and III diseases and juvenile GM2 gangliosidosis. This subject is reviewed in detail elsewhere.[1] Because these patients have cognitive dysfunction, they can be difficult to examine.

Acute hemisphere stroke can cause a transient gaze deviation in both head and eyes.[12] Usually, the eyes are deviated toward the side of the lesion (ipsiversive gaze deviation) because of paresis of gaze to the hemiplegic side. After about 5 days the intact hemisphere takes over and both the gaze paresis and ocular deviation resolve. Subsequently, subtle defects, such as prolonged saccadic latencies and impaired saccadic suppression, can be detected only by quantitative oculography. Other acute insults, such as head injury, also may result in such gaze palsies.

Ictal conjugate ocular deviation (seizure activity) occurs as a result of irritative lesions, which include trauma, tumors, or small cerebral hemorrhages. Such lesions “activate” the involved frontal eye field and cause the eyes to deviate away from the damaged hemisphere (adversive gaze deviation). Usually, such ocular deviation is associated with or immediately followed by adversive nystagmoid eye movements. It later is followed by postictal paralytic conjugate ocular deviation, in which gaze is deviated transiently toward the involved hemisphere, as part of Todd’s paralysis.

Acquired ocular motor apraxia, a term used loosely and often incorrectly, occurs in patients who have bilateral frontoparietal damage or diffuse bilateral cerebral disease, and is better termed saccadic paresis or palsy.[13] Head thrusts, if present, are not as conspicuous as in the congenital variety.[14]

The PPRF may be injured by a variety of lesions including ischemia, hemorrhage, neoplasm, infection, demyelination, and paraneoplastic disorders. A lesion that affects the ipsilateral abducens nucleus or PPRF causes an ipsilateral gaze palsy. A rostral PPRF lesion spares the VOR, whereas a caudal lesion does not. As a result of the proximity of the abducens nucleus and the facial nerve fasciculus, ipsilateral facial weakness typically occurs with caudal PPRF lesions. Rarely, the first-order (central) sympathetic fibers may be involved, causing an associated ipsilateral Horner’s syndrome.[15]

Wrong-way eyes is the term given to conjugate eye deviation to the “wrong” (hemiplegic) side, that is, away from the lesion and toward the hemiplegic side (contraversive gaze deviation). [16] It may occur with supratentorial lesions, particularly thalamic hemorrhage and, rarely, with large perisylvian or lobar hemorrhage or irritative lesions (below).

Incomplete lesions of the PPRF result in difficulty maintaining eccentric gaze and produce gaze-paretic, or gaze-evoked, nystagmus. When the eyes drift back to the primary position, the patient makes corrective saccades back to the eccentric target, which results in gaze-evoked nystagmus.

Bilateral lesions of the PPRF may cause complete loss of voluntary horizontal gaze. Large lesions may extend into the ventral pons, injuring the corticospinal pathways, and render the patient quadriplegic; this combination of findings is referred to as the locked-in syndrome.[17] Such patients appear unconscious, but volitional vertical eye and lid movements are spared, differentiating the locked-in syndrome from coma. Ocular bobbing can occur in this setting ( Chapter 202 ).

Spasticity of conjugate gaze is a horizontal conjugate deviation away from a large, deep parietotemporal lesion during forced eyelid closure, and it may be considered a variant of Bell’s phenomenon. Eye movements otherwise are normal.

Slow saccades occur with pontine disease as a result of burst cell dysfunction. Slow saccades also occur in patients who have some forms of cerebellar degeneration involving the pons and a number of disorders listed in Box 197-2 .[1] Some patients who have hypometric saccades (as in myasthenia, Huntington’s disease, brainstem encephalitis, and striatonigral degeneration) appear clinically to have slow saccades (pseudo–slow saccades).

Disorders of saccadic initiation result in prolonged latencies and occur in patients who have acquired immunodeficiency dementia complex, and or a variety of degenerative disorders of the nervous system, such as Alzheimer’s, Huntington’s, Parkinson’s, and Pick’s diseases.

Psychogenic ocular deviation may occur in patients who feign unconsciousness. The eyes are directed toward the ground irrespective of which way the patient is turned.

Disorders of Pursuit

The horizontal pursuit pathways control ipsilateral tracking. The final common motor pathway extends from the parieto–occipito–temporal junction, via the dorsolateral pontine nuclei, to the ipsilateral gaze center in the PPRF. With rare exceptions, lesions of the pursuit pathways cause impaired ipsilateral tracking; because the pursuit pathways probably decussate twice,[18] a unilateral midbrain lesion can cause impaired contralateral pursuit.[19] The frontal eye fields, superior colliculi, and cerebellum also contribute to pursuit drive.

Pursuit deficits range from absence of tracking eye movements to saccadic (cogwheel) pursuit. Global impairment of smooth pursuit is a common, nonspecific finding and can occur with medications (anticonvulsants, sedatives, or psychotropic agents), alcohol, fatigue, inattention, schizophrenia, encephalopathy, and a variety of neurodegenerative disorders, as well as age (infants

Causes of Slow Saccades

Acquired immunodeficiency syndrome dementia complex

Amyotrophic lateral sclerosis

Anticonvulsant toxicity (consciousness usually impaired)

Ataxia and telangiectasia

Hexosaminidase A deficiency

Huntington’s disease

Internuclear ophthalmoplegia

Joseph’s disease

Lesions of the paramedian pontine reticular formation

Lipid storage diseases

Lytico-Bodig’s disease

Myotonic dystrophy

Nephropathic cystinosis

Ocular motor apraxia

Ocular motor nerve or muscle weakness

Olivopontocerebellar degeneration

Progressive supranuclear palsy

Wernicke’s encephalopathy

Whipple’s disease

Wilson’s disease

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and the elderly), and occasionally with focal lesions in the parieto-occipital region (area 39).

Injury to the pursuit pathways also affects the slow phase of OKN, easily demonstrated by rotating an optokinetic drum so that the stripes move toward the affected hemisphere. Because of the proximity of the pursuit pathways to the afferent visual pathways, lesions here often are associated with a contralateral homonymous hemianopia.

Balint’s syndrome is characterized by these essential features: apraxia, inability to voluntarily look at different parts of the visual field; simultanagnosia, inability to attend simultaneously to different parts of the visual field; and optic ataxia, mislocalization when reaching for, or pointing to, objects. Bilateral hypoperfusion of the parieto-occipital region, usually as a result of a prolonged episode of hypotension, may case watershed (distal territory) infarction. Such patients may have some or all of the features of Balint’s syndrome including visual agnosia, visual disorientation, and difficulty in determining the direction, velocity, and distance of moving objects; they also may have pursuit defects.

Internuclear Ophthalmoplegia

Injury to the MLF, between the abducens nucleus and the contralateral medical rectus subnucleus of the oculomotor nerve, interrupts transmission of neural impulses to the ipsilateral medial rectus muscle (see Fig. 197-3 ). This impairs adducting saccades of the ipsilateral eye, which become either slow or absent. On attempted lateral gaze, away from the side of the lesion, the abducting eye overshoots the target (dysmetria), giving the appearance of dissociated (disconjugate) nystagmus. If the internuclear ophthalmoplegia (INO) is bilateral, abduction saccades also may be slow because of impaired inhibition of resting tone in the medial rectus muscle. Upward beating and torsional nystagmus are present frequently, particularly if both MLFs are affected. A subtle INO may be demonstrated when the patient makes repetitive horizontal saccades, which disclose slow adduction of the ipsilateral eye. Convergence may be preserved. Other clinical features associated with INO include skew deviation (with the hypertropic eye usually ipsilateral to the lesion), defective vertical smooth pursuit, impairment of the vertical VOR, as well as impaired ability to suppress or cancel the vertical VOR.

INO also may occur with a variety of disorders that affect the brainstem (vascular, demyelinating, and metastatic) and must be differentiated from the pseudo-INO of myasthenia or a long-standing exotropia.

The one-and-a-half syndrome occurs with damage to the caudal dorsal pontine tegmentum that involves the ipsilateral MLF and either the ipsilateral PPRF or the abducens nucleus results in an ipsilateral gaze palsy with an ipsilateral INO (see Fig. 197-3 ). The only horizontal movement left intact is abduction of the contralateral eye. If the facial nerve nucleus or fasciculus is involved, oculopalatal myoclonus (a vertical oscillation of the eyes, palate, and other muscles of branchial origin) may develop later.[20] The most common causes of the one-and-a-half syndrome are multiple sclerosis and brainstem stroke, followed by metastatic and primary brainstem tumors.[21] Ocular myasthenia may cause a pseudo–one-and-a-half syndrome.[22]

Disorders of Vertical Gaze

Isolated midbrain lesions can cause disorders of vertical gaze (see Fig. 197-4 ) and occur with a variety of diseases ( Box 197-3 ). Disorders of vertical gaze, particularly downgaze, often are overlooked in patients with brainstem vascular disease, because damage to the nearby reticular activating system impairs consciousness.

Supranuclear upgaze palsies occur with lesions at or near the posterior commissure and with bilateral lesions in the pretectal

Disorders of the Midbrain That Affect Vertical Gaze

EXTRINSIC LESIONS

Pineal region tumors

Vascular malformations and aneurysms

Hydrocephalus (failed ventricular shunt)

Parasitic cysts

INTRINSIC LESIONS

Primary brainstem tumor (glioma, ependymoma)

Metastatic brainstem tumor

Third ventricular tumors

Pituitary adenomas

Stroke

• Infarction

• Hemorrhage (thalamic, pretectal)

Trauma (surgery, head injury)

Multiple sclerosis

Infection (syphilis, encephalitis)

Lipid storage disease

Transtentorial herniation

Kernicterus

Wernicke’s syndrome

Bassen-Kornzweig’s syndrome

Vitamin B12 deficiency

Jejunal ileal bypass

area (see Fig. 197-4 ). With supranuclear disorders of vertical gaze, saccades are usually impaired initially, followed by pursuit and then loss of vertical VORs. Extrinsic compression of the posterior commissure or pretectal region also causes loss of the pupillary light reflex, but accommodation and convergence are preserved (light–near dissociation). Paralysis of upgaze, light–near dissociation of the pupils, impaired convergence, lid retraction, and convergence retraction nystagmus are features of the dorsal midbrain (Parinaud’s) syndrome.

Convergence–retraction nystagmus is a uniquely localizing sign of injury to the dorsal midbrain region. It is not true nystagmus but a saccadic disorder[3] that is elicited best by rotating an optokinetic drum with the stripes moving downward. When the patient attempts to make corrective upward saccades to refixate, the eyes converge and retract in the orbits because of synchronous cocontraction of the extraocular muscles.

Downgaze palsy occurs with bilateral lesions of the rostral interstitial nucleus of the MLF or its projections (see Fig. 197-4 ). With the exception of occlusion of the posterior thalamosubthalamic branch of the posterior cerebral artery (Percheron’s artery), such discrete lesions are rare; involvement of the midbrain rather than the thalamus is responsible for the paralysis.[23] More commonly, bilateral involvement of the pathways for downgaze, and also for upgaze, occurs as part of diffuse disorders such as progressive supranuclear palsy, Whipple’s disease, neurovisceral lipid storage disorders, complications of acquired immunodeficiency syndrome, and so on. Rarely, a unilateral lesion of the midbrain tegmentum may result in impaired downward, as well as upward, saccades.[24]

Progressive supranuclear palsy, also called the Steele-Richardson-Olszewski syndrome, is a neurodegenerative disorder that appears in about the sixth decade. It is characterized by vertical supranuclear gaze palsy, particularly for downward eye movements, postural instability, and unexplained falls. In addition, nuchal rigidity, Parkinsonism, pseudobulbar palsy, and mild dementia may be present. Early visual symptoms include blurred vision (making it difficult to see food on a plate and to read), diplopia, burning eyes, and photophobia. As the disease progresses, horizontal eye movements become impaired, as well, and eventually a global gaze paresis develops. [3]

Wilson’s disease, or hepatolenticular degeneration, is associated with a Kayser-Fleischer ring, caused by the accumulation of

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copper in Descemet’s membrane. Eye movement abnormalities are unusual, but saccades may be slowed and a supranuclear upgaze palsy may occur.

Kernicterus, or neonatal jaundice, can cause upgaze paresis, which usually is supranuclear.[25] Horizontal saccades may be slow.

Niemann-Pick’s disease type C, or juvenile dystonic lipidosis, may be associated with supranuclear palsy for downgaze, ataxia, athetosis, and foamy macrophages (the DAF syndrome). This disorder can have an early onset during the first year of life, when it is associated with developmental delay, ataxia, vertical gaze palsy, and mental retardation. The more common form has a delayed onset and is associated with cerebellar ataxia or dystonia at around 3 years of age; then a vertical gaze palsy and cognitive difficulties begin at around 6 years of age. The diagnosis consists of the demonstration of decreased cholesterol esterification in skin fibroblasts, as well as the demonstration of unusual, large, vacuolated storage cells in the bone marrow.

Huntington’s disease also affects eye movements. Patients find it difficult to initiate saccades and frequently use blinks and head thrusts to facilitate eye movements. Voluntary saccades are slow, hypometric, and have long latencies, and vertical saccades are affected more than horizontal saccades. Fixation instability is prominent because of the inability to suppress spontaneous and reflex saccades as a result of frontal lobe disease. Smooth pursuit is spared relatively, except for interruption by square wave jerks.[26]

Tonic upward deviation of gaze, or forced upgaze, is rare but may be seen in unconscious patients.[27] It occurs with diffuse brain injury (hypotension, cardiac arrest, and heatstroke) and must be differentiated from oculogyric crises, petit mal seizures, and psychogenic coma. Some patients may develop myoclonic jerks and large-amplitude downbeat nystagmus; the prognosis for life is extremely poor. Rarely, tonic upward gaze deviation may be psychogenic, but it can be overcome, indeed cured, by cold caloric stimulation of the semicircular canals.

Benign paroxysmal tonic upward gaze usually starts during the first year of life, lasts about 2 years, and has no known cause. Episodes last for seconds to hours and may occur in young children with ataxia and downbeat nystagmus on attempted downgaze. This phenomenon can occur with cystic fibrosis.[28] There is little evidence to suggest that these are either seizures or oculogyric crises (see below). Tonic upgaze also may be seen in normal infants during the first months of life.[29]

Tonic downward deviation of gaze, or forced downgaze, is associated with medial thalamic hemorrhage, acute obstructive hydrocephalus, severe metabolic or hypoxic encephalopathy, or massive subarachnoid hemorrhage. When associated with lid retraction, the corneas can be buried below the lower lid (sundowning). In this setting, elevated intracranial pressure is a major concern. The eyes may be converged, as if looking at the nose. Large thalamic hemorrhages may be associated with tonic downgaze, miotic pupils, esotropia,[3] [30] skew deviation, and an ipsilateral gaze preference.[30] Preterm infants with intraventricular hemorrhages also may have tonic downward deviation with a skew and esotropia.[31]

Tonic downward deviation of the eyes may occur as a transient phenomenon in otherwise healthy neonates. It also can be induced in infancy by sudden exposure to bright light. Tonic downward gaze deviation may occur with psychogenic illness, but it can be overcome by caloric stimulation of the semicircular canals. Tonic vertical deviation as a result of seizure activity is rare.

Skew deviation is a vertical divergence of the ocular axes caused by a “prenuclear” lesion of the vertical vestibulo-ocular pathways in the brainstem or cerebellum. About 12% of patients who have skew deviation alternate on lateral gaze (see below) or spontaneously. Skew deviation usually, but not always, is comitant and frequently is associated with cyclotorsion of one or both eyes. When the skew deviation is noncomitant it can mimic a partial third or a fourth cranial nerve palsy. Skew deviations occur most commonly with vascular lesions of the pons or lateral medulla (Wallenberg’s syndrome). Brandt and Dieterich [32] demonstrated ocular torsion of one or both eyes associated with a subjective tilt of the visual vertical toward the lower eye in most patients who have skew deviations. With lesions of the midbrain or upper pons, the contralateral eye was lower (contraversive skew), but with lesions of the lower pons or medulla the ipsilateral eye was lower (ipsiversive skew).

When patients have alternating skew deviation, the hypertropia changes with the direction of gaze. The adducting eye usually is hypotropic, thus mimicking superior oblique overaction. Alternating skew deviation occurs with lesions of either the upper midbrain region involving the interstitial nucleus of Cajal or the cervicomedullary junction or cerebellum; in the latter situation, ataxia and downbeat nystagmus usually are associated.[33]

Less commonly, alternating skew deviation may mimic bilateral superior oblique palsies; however, measurement of the deviations on head tilt, detection of a V pattern, and the degree of subjective and objective cyclotorsion also help to differentiate the two conditions. Furthermore, associated neurological findings and the clinical context are more definitive.

Paroxysmal or periodic alternating skew deviation occurs with midbrain lesions; the hypertropia changes in a regular or irregular manner over periods of seconds to minutes. Other features of the dorsal midbrain syndrome may be present.

Ocular counter-rolling is a normal vestibular eye reflex that allows people to maintain horizontal orientation of the environment while the head tilts to either side (see Fig. 197-2 ). When the head is tilted to the left, the left eye rises and intorts as the right eye falls and extorts.

The ocular tilt reaction consists of the triad of skew deviation, cyclotorsion of both eyes, and paradoxical head tilt, all to the same side—that of the lower eye (see Fig. 197-2 ). A tonic (sustained) ocular tilt reaction occurs with lesions of the ipsilateral utricle, vestibular nerve or nuclei, or a lesion in the region of the contralateral interstitial nucleus of Cajal and medial thalamus. A phasic (paroxysmal) ocular tilt reaction occurs with lesions of the ipsilateral interstitial nucleus of Cajal and may respond to baclofen.

Dissociated vertical deviation is an asymmetrical, bilateral phenomenon that occurs with early disruption of fusion (congenital esotropia, infantile cataract). Usually, it is manifest during periods of inattention, in which the deviating eye elevates, abducts, and excyclotorts. The cause remains unclear, but it is one of the few exceptions to Hering’s law of equal innervation. When manifest, it is best treated by unilateral or bilateral superior rectus recession.[34] Dissociated horizontal deviation also occurs and is probably simply a variant of dissociated vertical deviation.

Congenital monocular elevator deficiency, previously known as double elevator palsy, is characterized by congenital limitation of elevation of one eye. Most patients are hypotropic in the primary position but use a chin-up head position to allow fusion. A ptosis or pseudoptosis, in which the upper lid of the affected hypotropic eye appears ptotic because the eye is lower, almost always is present. Monocular elevator deficiency is believed to result from a prenuclear congenital unilateral midbrain lesion because the affected eye usually is elevated by Bell’s reflex. Furthermore, because the elevator muscles of the affected eye (inferior oblique and superior rectus) are innervated by their respective subnuclei within the third cranial nerve nucleus, but on opposite sides of the midline ( Chapter 198 ), a single unilateral lesion must be prenuclear rather than nuclear.

In long-standing monocular elevator deficiency, the inferior rectus muscle may become tight, which may be treated using recession. If no restriction occurs, a full tendon vertical transposition (Knapp procedure) of the horizontal muscles is recommended.[35] Other disorders that may cause inferior rectus restriction, such as thyroid orbitopathy and orbital floor fractures, must be excluded.

Monocular supranuclear (prenuclear) elevator palsy is an acquired limitation of elevation of one eye on attempted upgaze.

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Patients remain orthotopic in primary position and downgaze is intact. This disorder occurs with unilateral vascular[36] or neoplastic[37] lesions of the midbrain. The affected eye usually is elevated by Bell’s reflex or by vestibular stimulation.

Oculogyric crises are spasmodic conjugate ocular deviations, usually upward but sometimes lateral, which occur most frequently after the use of neuroleptic medication, particularly haloperidol. A typical attack or crisis occurs for about 2 hours, during which the eyes deviate tonically upward, repetitively, for periods of seconds to minutes. The spasms may be preceded or accompanied by disturbing emotional symptoms, including anxiety, restlessness, compulsive thinking, and sensations of increased brightness or distortions of visual background.

OCULAR MOTILITY DISORDERS AND THE CEREBELLUM

The cerebellum coordinates the different motor and sensory inputs to the ocular motor system and ensures that the eyes move smoothly and accurately. Ocular motility signs indicative of cerebellar disease are listed in Box 197-4 . The dorsal vermis and fastigial nuclei determine the accuracy of saccades by adjusting their amplitude. Lesions of the dorsal vermis and fastigial nuclei result in saccadic dysmetria. The flocculus is responsible for the stabilization of images on the fovea, particularly after a saccade. Lesions of the flocculus result in gaze-holding deficits, such as gaze-evoked, rebound, or downbeat nystagmus, impaired smooth pursuit, inability to cancel the VOR by the pursuit system, and inability to suppress nystagmus (and vertigo) by fixation. The nodulus influences vestibular eye movements and vestibulo-optokinetic interaction. Lesions of the nodulus may produce periodic alternating nystagmus.

Posterior fossa tumors may become apparent with strabismus; acute comitant esotropia may be the first sign.[38] Children who have such tumors usually are older than those who have infantile or accommodative esotropia, and they develop nystagmus or other neurological signs at a later date.[39] Failure to regain fusion after spectacle, prism, or surgical therapy is a universal finding.[38]

A variety of ocular motility disorders may be associated with congenital or acquired defects of the cerebellum. Patients with COMA may have midline cerebellar defects.[40] Chiari malformations may be associated with downbeat nystagmus, gaze-evoked nystagmus, skew deviation, or esotropia. Familial cerebellar degeneration may be associated with vergence disorders.[41]

OCULAR MOTILITY DISORDERS AND THE VESTIBULAR SYSTEM

The vestibular system stabilizes the direction of gaze during head movements by adjusting tonic innervation to the ocular motor nuclei and, consequently, the extraocular muscles, thus maintaining a stable image on the retina. Each vestibular end organ has three semicircular canals, as well as a utricle and saccule.

The utricle and saccule are gravity receptors that respond to linear acceleration and static head tilt (gravity). Each semicircular canal projects to the vestibular nuclei and brainstem. Excitatory projections innervate pairs of yoked agonist extraocular muscles via their subnuclei (see Fig. 197-3 ), while inhibitory projections innervate their antagonists. Essentially each extraocular muscle subnucleus receives excitatory projections from one semicircular canal and inhibitory projections from the rival semicircular canal. This network is discussed in greater detail elsewhere[42] [43] but is illustrated most clearly by the horizontal VOR (see Fig. 197-3 ). The ampulla of the right horizontal semicircular canal is stimulated by turning the head to the right (or by warm caloric water irrigation). This mechanical information is transduced by the vestibular end organ into electrical signals and transmitted to the ipsilateral medial vestibular nucleus. Excitatory information then is relayed to the contralateral abducens nucleus (which sends projection to the ipsilateral medial rectus subnucleus), and inhibitory information to the ipsilateral abducens nucleus (which projects to the contralateral medial rectus subnucleus), and causes the eyes to deviate in the direction opposite to head rotation. Disruption of the pathways that subserve the vertical VOR (peripheral vestibular system, vestibular nuclei, cerebellar inputs, MLF, or cranial nerve subnuclei) causes a skew deviation.

VERGENCE DISORDERS

Convergence paralysis occurs with midbrain lesions and may be associated with other features of the dorsal midbrain syndrome. Lack of effort, however, is the most common cause of poor convergence. Degenerative disorders, such as cerebellar degeneration, Parkinson’s disease, and progressive supranuclear palsy, also may be associated with poor convergence. The absence of other midbrain signs and the lack of pupillary constriction on attempted convergence may differentiate psychogenic convergence paralysis from organic disease.

Convergence insufficiency is an idiopathic condition that also may in part be related to effort. It is seen in young individuals who complain of diplopia in association with prolonged near work. Symptoms include eyestrain, headache, and asthenopic complaints, such as burning eyes.[41] Rarely, it may follow closed head injury. Convergence fusional amplitudes often are diminished but can be improved with orthoptic exercises (pencil pushups).

Divergence insufficiency is characterized by uncrossed horizontal diplopia at distance in the absence of other neurological symptoms or signs. Patients have intermittent or constant esotropia that is present only at distance. Versions and ductions are full and saccadic velocities, if measured quantitatively, are normal, but fusional divergence amplitudes are reduced. The origin of divergence insufficiency is unclear, but it may result from a break in fusion later in life, follow a trivial insult, be seen in a patient with a prior esophoria, or occur in patients with cerebellar degeneration. The condition is treated easily with base-out prisms for the distance correction and rarely requires extraocular muscle surgery.

Divergence paralysis is a controversial entity that may be difficult to differentiate from divergence insufficiency and bilateral sixth cranial nerve palsies, but usually it occurs in the context of severe head injury or other cause of raised intracranial pressure. Such patients usually have horizontal diplopia at distance, but abducting saccades are slow. Divergence paralysis can occur with Fisher’s syndrome, Chiari malformations, pontine tumors, and diazepam therapy. Patients who have bilateral sixth cranial nerve palsies and who recover gradually may go through a phase in which the esotropia is comitant and versions are full, and thus mimic divergence paralysis.

Spasm of the near reflex is characterized by intermittent episodes of convergence, miosis, and accommodation and can

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mimic bilateral, and occasionally unilateral, abducens paresis. Symptoms include double or blurred vision. The patient is esotropic, particularly at distance, and has extreme miosis. Spasm of the near reflex occasionally occurs with organic disorders but is more commonly psychogenic in origin. The differential diagnosis is that of esotropia, but miosis and blurred vision during motility testing clinches the diagnosis. Patients who have psychogenic spasm of the near reflex often have associated somatic complaints and behavioral abnormalities, which include blepharoclonus on persistent lateral gaze, poor cooperation in the performance of motor tasks such as smiling, opening the mouth, and protruding the tongue, and other features of neurasthenia and asthenopia. Treatment first requires identification of the source of the psychopathology and its management, as well as reassurance as to the lack of ocular pathology. Cycloplegic agents, used to prevent accommodative spasm and thus inhibit the near triad, are rarely effective. Opacification of the inner one third of spectacle lenses is not effective. The effect of using minus (negative) spectacles is paradoxical and will worsen the deviation, so is contraindicated. Occasionally, a patient with uncorrected high hyperopia will appear to have spasm of the near reflex; however, a careful cycloplegic refraction will reveal an accommodative esotropia that was precipitated or unmasked as the patient’s divergence fusional amplitudes decreased with age. In such cases the correct management consists of prescribing the full cycloplegic refraction.

Central disruption of fusion, also called posttraumatic fusion deficiency, occurs after moderate head injury and causes intractable diplopia, despite the patient’s ability to fuse intermittently and even achieve stereopsis briefly. [42] The diplopia fluctuates and may be crossed, uncrossed, or vertical, and versions and ductions may be full, but vergence amplitudes are reduced markedly. Prism therapy or surgery is ineffective. Central disruption of fusion is caused by midbrain injury and may be associated with brainstem tumors, stroke, neurosurgical procedures, removal of long-standing cataracts, and uncorrected aphakia. This condition must be differentiated from psychogenic disorders of vergence and bilateral superior oblique palsies; the latter usually cause intolerable torsion. Inability to fuse also can occur in patients with infantile or early onset esotropia, congenital media opacities, and high degrees of anisometropia.

The hemislide phenomenon occurs when patients who have large visual field defects, particularly dense bitemporal hemianopias, develop diplopia. They have difficulty maintaining fusion because they can no longer suppress any latent deviation as a result of loss of overlapping areas of field.

Cyclic esotropia, also called circadian, alternate-day, or clock mechanism esotropia, begins in infancy or childhood. The cycles of orthotropia and esotropia have periods in the range of 24–96 hours. Most eventually develop constant esotropia and respond well to bimedial rectus muscle recession.

Ocular neuromyotonia is a brief, involuntary, intermittent myotonic contraction of one or more muscles supplied by the ocular motor nerves, most commonly the third cranial nerve. Although the mechanism is unclear, but most likely injury at a nuclear or infranuclear level, it is included here because it must be differentiated from other vergence disorders. Ocular neuromyotonia usually results in esotropia of the affected eye, with accompanying failure of elevation and depression of the globe, and may be provoked by prolonged eccentric gaze. It may be associated with signs of aberrant reinnervation of the third cranial nerve. Usually, the pupil is fixed to both light and near stimuli. Causes include radiation therapy and, less commonly, compressive lesions such as cavernous sinus meningiomas, pituitary adenomas and, rarely, dolichoectatic vessels. Occasionally no cause is found. Ocular neuromyotonia responds to carbamazepine and other antiepileptic drugs and must be differentiated from superior oblique myokymia and the spasms of cyclic oculomotor palsy ( Chapter 202 ).

DEVELOPMENT OF THE OCULAR MOTOR SYSTEM

Maturation of the infant nervous system continues after birth and is particularly rapid during the first few months of life. At birth the vestibular system is the most developed of the ocular motor subsystems and may be tested by rotating the infant (held at arm’s length) with the head tilted 30 degrees forward. The VOR is well developed by the end of the first postnatal week.[43] Smooth pursuit movements occur in neonates, but only with large targets (such as a human face) that move at low velocities, because the fovea is not well developed at this stage. The pursuit system does not mature fully until the late teens. The saccadic system also is immature in the neonate. Vertical saccades mature more slowly than horizontal saccades and may not be detected for the first month after birth. Vergence movements are also slow to mature but are seen after about the first month.

Transient Ocular Motility Abnormalities in Infancy

Several benign transient ocular motility disorders occur in infancy. Neonatal strabismus occurs in up to one third of healthy neonates; an esotropia that persists beyond 3 months, or an exotropia that persists beyond 4 months, postnatally is abnormal.[44] Tonic downward ocular deviation occurs in approximately 2% of otherwise healthy neonates[45] [46] and is similar to the “sun-setting” sign seen in infants who have hydrocephalus, but resolves spontaneously. Lid retraction, either spontaneous or associated with sudden darkness, may be noted. Tonic upgaze is much rarer than tonic downgaze but is well described[31] [47] and, also, usually resolves. Skew deviation occurs in healthy infants and usually resolves[45] ; however, a substantial number of them develop strabismus. Some neonates may have a transient horizontal gaze palsy (Donahue, personal observation, 1995).

Premature infants, especially those with intraventricular hemorrhages, may develop tonic downward and esotropic ocular deviations similar to the motility findings in adults who have acquired thalamic lesions. Although the upgaze palsy typically resolves, the esotropia persists and requires surgery.[28]